Prognostic factors in surgically treated tongue squamous cell carcinoma in stage T1‐2N0‐1M0: A retrospective analysis

Abstract Purpose The study aimed to retrospectively identify the prognostic factors of surgically treated primary tongue squamous cell carcinoma (TSCC) cases and assess the benefits of surgical neck lymph node dissection (LND) in early‐stage cancer. Methods Patients with primary TSCC with pT1‐2N0‐1M0 stage without distant metastasis who were treated with surgery during 2014–2016 at Xiangya Hospital, Central South University were included. Univariate and multivariate Cox models were constructed to explore prognostic factors of overall survival (OS), disease‐free survival (DFS), and local recurrence‐free survival (LRFS). Sub‐group analysis was used to assess the effect of adjuvant therapy and the prognostic value of LND for the early‐stage patients. Results In total, 440 patients met the inclusion criteria. During the follow‐up period, the 5‐year OS, DFS, were 84.4% and 70.0%, respectively. Univariate analysis showed that TNM stage, lymphovascular invasion (LVI), and/or perineural invasion (PNI), pathological differentiation, etc. were significant predictors of OS and DFS. Multivariate analysis showed that TNM stage and the degree of pathological differentiation were independent prognostic factors for all outcomes. Besides, the number of cervical LND could independently predict both DFS and LRFS while LVI/PNI were associated with DFS. And high‐quality neck LND (≥30) significantly improved DFS and LRFS for patients of pT1cN0M0 or stage I as compared to those without LND. Conclusions TNM stage and pathological differentiation were crucial prognostic factors for postoperative patients with TSCC. Notably, high‐quality cervical LND was beneficial for the improvement of DFS and LRFS for patients of pT1cN0M0 or stage I.


| INTRODUCTION
Data from GLOBALCAN indicates that an estimated 377,713 people had oral or lip cancer during 2020, among which around 46% (177,757) patients died. 1 Although oral cancer is not among the highest cancer-associated mortality, facial disfigurement, loss of speech, and eating function caused by the disease and its treatment can cause profound morbidity and negative effects on patient quality of life.Established risk factors of oral cancer include tobacco smoking 2 and alcoholism. 3Betel nut chewing has been identified as a major risk factor for oral cancer incidence in areas with high betel nut consumption, such as the Indian subcontinent and Taiwan. 4There is also a high incidence of oral cancer in Hunan province, China, where betel nut is commonly used.
Oral tongue squamous cell carcinoma (TSCC), which arises at the anterior two thirds of the tongue, is the most common malignancy diagnosed within the oral cavity. 5Treatment of TSCC includes comprehensive management including surgery with or without radiotherapy and chemotherapy.[8][9][10] According to the 2022 National Comprehensive Cancer Network (NCCN) guidance, surgery remains the major treatment option, including for some patients with III-IV stage, reflecting its governing position in oral cancer therapy. 11ymph node metastasis is the most well-recognized prognostic factor in negative oral cancer prognosis. 12thers 13 have demonstrated that pN stage plays a predominant role in outcomes of patients with TSCC treated with primary surgery and appropriate adjuvant therapy.However, the issue of lymph node dissection (LND) in oral cancer patients in early stage has been the subject of much discussion. 14Tumor grade, depth of invasion, and subsite are crucial factors for assessing the benefit of elective neck dissection in such early-stage oral cancer cases. 15he choice of whether and how to perform lymphatic dissection, especially for patients with oral cancer T1N0M0 merits further investigation.
In the present study, we analyzed data from 440 primary TSCC patients with pT1-2N0-1M0 stage treated at Xiangya Hospital during 2014-2016 to identify the predictors of patient outcomes and further explore the effects of LND in early-stage cancer.

| Patient selection
Consecutive patients with TSCC who were categorized as code C02 according to the International Classification of Disease for Oncology, 10th revision (ICD-10) were selected from the medical record system of Xiangya Hospital, Central South University, Hunan, China.The inclusion criteria were as follows: newly diagnosed TSCC patients with stage pT1-2N0-1M0 who underwent surgical resection from January 1, 2014 to December 31, 2016.Exclusion criteria were as follows: patients who were diagnosed with tongue base cancer; histological diagnosis not consistent with squamous cell carcinoma; patients who did not undergo surgery in the study center hospital or had received treatment prior to reporting to the study center; patients who had secondary cancer or patients who had distant metastasis; patients who had postoperative chemotherapy alone; patients who did not have complete clinical records in the hospital medical record system.A total of 440 consecutive patients who fulfilled the abovementioned criteria were included retrospectively in the study.The study protocol was reviewed and approved by the Ethical Review Committee of the Xiangya Hospital Central South University, Hunan, China (202212296).

| Data collection
Patient characteristics including age, gender, admission time, surgical information, pathological diagnosis, and application of adjuvant therapy if any and its type, were recorded.TSCC TNM staging was categorized based on 7th American Joint Committee on Cancer (AJCC) classification system.

| Follow-up protocol
Telephonic follow-up was primarily used to acquire information from patients and their caregivers, including their current condition, further treatment received, concomitant disease conditions, relapse, salvage treatment, and death.For those patients who could not be contacted, information was collected from hospital outpatient records and imaging records to note any disease recurrence.The date of surgery at Xiangya Hospital was considered the baseline event for the study, and the endpoints varied for different outcomes.For overall survival (OS), death, and the last follow-up were considered as endpoint.For disease-free survival (DFS), the endpoints were death, recurrence, or the last follow-up.For local recurrence-free survival (LRFS, including local and regional lymph node recurrence) and distant metastasisfree survival (DMFS), the endpoints were last follow-up/ death or local-regional recurrence or distant recurrence, respectively.The follow-up duration was counted in months from the date of primary surgery to August 2021 or the date of last known event.

| Statistical analysis
Data were analyzed using SPSS (v22.0,IBM Corporation, USA) and R (version 4.3.0).Univariate and multivariate Cox analyses were applied to evaluate the potential prognostic factors related to survival outcomes including OS, DFS and LRFS.Kaplan-Meier survival analysis and logrank test were used to compare various survival curves.Then, we divided patients into groups according to T or N stage and sub-group analysis was performed to compare survival outcomes of patients with or without adjuvant therapy, or with various numbers of LND.Count data were analyzed by chi-square test.The results are presented as hazard ratios (HR) with 95% confidence interval (95% CI), and p < 0.05 was recognized as statistically significant.

Cases
The median follow-up time was 61 months (range 0.5-91 months).Among all the patients, 379 cases survived and 61 cases died, of which 53 patients died from primary tumor, 4 patients died from secondary tumors, 3 patients died of other reasons like cardiovascular diseases, and 1 died of an undefined reason.In addition, a total of 119 cases had TSCC-related progression after surgery, including 107 cases with loco-regional recurrence only, 8 cases with distant metastasis (DM) only, 4 cases with both local-regional failure and DM.One patient with lost follow-up were defined as survival of 0.5 months after surgery.
3.2 | Prognostic factors in postoperative TSCC patients
The multivariate Cox analysis included three factors for LRFS (TNM stage, degree of pathological differentiation, LVI, and/or PNI).We found that the TNM stage (p < 0.05), the number of LND (p = 0.002) and pathological differentiation (p = 0.001) were all independent risk factors for LRFS (Table 3).Since only 12 patients had distant metastasis, we did not include this factor in the univariate and multivariate analysis for DMFS.

| Sub-group analysis of adjuvant therapy
The NCCN guidelines recommend adjuvant radiotherapy or chemoradiotherapy for patients with advanced clinical features like LVI/PNI, locally advanced stage, etc.In this study, there were 51.6% patients with stage I, 25.9% with stage II and 22.5% with stage III disease.Under univariate Cox analysis, postoperative adjuvant therapy was not significantly associated with OS, DFS, or LRFS (all p > 0.05, Tables S1 and S2).However, as disease stage is an important correlate of treatment choice and outcome, sub-group analysis was performed to explore the effect of adjuvant therapy.We first selected patients with pT2 and pN1, then by comparing patients with or without postoperative adjuvant therapy, we found that RT/CRT tended to increase LRFS for patients of pT2 or pN1 (Table S3, Figure 1).Whereas in the remaining analysis, patients with or without postoperative adjuvant therapy showed no significant differences in OS, DFS, or LRFS, (p > 0.05, Table S3).

| Effect of cervical LND for pT1cN0-1M0 or stage I TSCC patients
In this study, 41 out of 267 (15.4%) patients in pT1 stage and 6 out of 173 (3.5%) patients in pT2 stage did not undergo neck LND.To explore the function and effects of LND, we first collected patients of pT1cN0 or stage I. Then we categorized patient into four groups according to the number of LND: 0 (without LND), <15, 15-29, and ≥30.For pT1cN0 patients, we found that LRFS was significantly different between patients with or without LND (Table 4, Figure 2, p < 0.05).Furthermore, the DFS and LRFS for those who had ≥30 LND was significantly higher T A B L E 3 Multivariate analysis of predictors of LRFS for pT1-2N0-1M0 TSCC patients.
than of those without LND and tended to be higher than those <15 or 15-29 cervical LND (p = 0.007, 0.106, 0.067, respectively for DFS and p = 0.003, 0.088 and 0.086 respectively for LRFS, Table 4).However, there was no significant improvement for OS in pT1cN0 patients with or without LND (Table S4).
For patients with stage I TSCC, the LRFS and DFS were significantly different between patients with various numbers of LND (Table 4, Figure 2, p < 0.05).The LRFS was lower in those without cervical LND than those with <15, and ≥30 LND (p = 0.026, 0.005, respectively).Furthermore, the 5-year DFS was worse for patients without cervical LND compared to those with ≥30 of LND (p = 0.005).However, similar results were not observed when comparing OS (Table S4).
By analyzing the pattern of recurrence in patients of pT1cN0 or stage I. we also found that the patients in the group without LND had more frequent local and lymph node recurrence (p = 0.009, p = 0.042).When LND was ≥30, those patients not only had the lowest ratio of regional lymph node recurrence but also the least local recurrence.(Table S5, p < 0.05).

| DISCUSSION
This was a single-center retrospective study that included a large number of patients with TSCC collected over the course of a relatively short period of time (2014-2016).7][18] More than 85% of the patients in our study had a history of betel nut consumption, smoking, or drinking.The 5-year OS, DFS, and LFRS of the whole group in T1-2N0-1 were 84.4%,70.0%,and 74.5%, respectively.Most of the recurrence events happened in the first 2 years (76.6%) which indicates that regular follow-up is critical.Earlier retrospective studies of postoperative TSCC have reported slightly lower survival rates.Ganly et al. 19 analyzed 216 patients  with postoperative cancer in the early stage over 20 years and found the 5-year OS and RFS were 79% and 70%, respectively.Similarly, Fridman et al 20 analyzed 1257 patients of oral cavity squamous cell carcinoma in stage T1-2N0 (T1: 36.7%,T2: 63.3%) after surgery and reported the 5-year OS, DFS, disease-specific survival (DSS), and LRFS were 75%, 73%, 83%, and 79%, respectively.Besides, Daniell et al. 21also reported a similar distribution (T1: 53%, T2: 35%) with a 69% 5-year OS and a 75% 5-year freedom from loco-regional failure of 258 patients with postoperative TSCC from 2007 to 2016.In the present study, 89.3% of the patients received LND, with 50.2% having >15 LND.The rate of pathological positive margins or LVI/PNI were relatively low (2.3% [10/440] cases and 9.5% [42/440], respectively).Overall, the results of this study can be considered representative of the outcomes of radical resection in TSCC populations with a high prevalence of betel nut chewing and thus provide valuable clinical reference.
3][24] In accordance, the present study found that pTNM stage was an independent prognostic factor of OS, DFS, and LRFS.Besides, pT and pN stage also have been reported as independent risk factors of OS and disease-specific survival for patients with oral cancer, 13,25 which is consistent with our finding that stage pT and pN were associated with OS and DFS.Furthermore, pN stage has also been found to be predictive of OS in TSCC after surgery 19,26 and emerged as a key predictor of survival outcomes.In the present study, patients with pN0 and pN1 stage had 5-year OS of 88.4% and 69.9%, with the 5-year DFS of 73.5% and 57.4%, respectively (data not shown).These results revealed that advanced stage at time of surgery predicted worse outcomes and highlighted the need for early diagnosis and timely treatment.
A high-quality cervical LND involve at least 18 lymph nodes for the patients of oral cancer. 27In the whole group, the median number of LND was 15.We divided patients into four groups according to numbers of LND (0 [without LND], <15, 15-29, and ≥30) and performed multivariate analysis.The results showed that LND was found to be an independent predictor for DFS and LRFS.We also noted that the DFS and LRFS of patients with ≥30 LND was significantly higher than those without LND.However, the number of LND did not affect OS.These findings suggest that for TSCC patients of stage T1-2N0-1, high quality of LND may help to avert early disease recurrence.Elective dissection of cervical lymph nodes during surgical management of early-stage oral cancer has been a subject of debate.The ASCO clinical practice guidelines suggest that LND can be performed for oral cancer patients with T1N0M0 along with close ultrasound surveillance. 27thers have proposed that observation rather than dissection or adjuvant therapy should be recommended for patients with T1-2N0 oral cancer without neural or vascular invasion. 28A meta-analysis showed that for patients with T1-2N0 OTSCC, LND can significantly prevent local recurrence and thus increase disease specific survival but not OS. 29Another meta-analysis including 1250 patients (7 randomized controlled trials) in early-stage OSCC with clinical N0 patents found that in comparison to observation, elective neck dissection could significantly improve OS and DSS, and significantly reduce lymph node recurrence. 30Furthermore, the number of LND is also important for better outcome.Cheng et al. 31 noted that the survival outcome was significantly higher in the group with ≥37 retrieved lymph nodes for patients of T1-2N0M0 oral cancer.In the present study, we found that the DFS and LRFS were significantly higher in patients with stage pT1cN0M0 or stage I when LND ≥30, whereas those without LND had the lowest DFS and LRFS, and local and regional recurrence rates.To further explore the correlated of recurrence, we confirmed the findings with chi-square test which showed that when LND ≥30, both local and lymph node recurrence was lower as compared to those without LND.However, OS was not improved by LND, which may be due to the fact that disease recurrence did not cause death for patients of stage pT1cN0 and stage I, and the 5-year OS in these patients remained as high as over 90%.Above all, these findings indicated that not only for patients with TSCC in stage T1-2N0-1 but also for those with stage pT1cN0 or stage I, high quality of LND (≥30) was beneficial for DFS and LRFS and thus should be considered at the first surgery.
The NCCN guidelines describe LVI/PNI as adverse pathologic and prognostic features. 32The presence of LVI/ PNI is associated with a worse prognosis in TSCC, 9,13,25,[33][34][35] especially for those who had multifocal intra-and peritumoral PNI. 36LVI was also reported be associated with cervical lymph node metastasis and loco-regional recurrence. 37atients with pN0 stage oral cancer 38 or TSCC 39 with LVI/ PNI show worse loco-regional control and OS, suggesting the need for further adjuvant therapy.In this study, the incidence of LVI and PNI was 2.3% and 9.5%, respectively.The univariate analysis results showed that LVI/PNI predicted worse OS, DFS and LRFS.LVI/PNI also tended to decrease DFS in the multivariate Cox analysis (p = 0.060).The insignificant result may be due to the substantial difference in sample size between the two groups but the trend suggested that LVI/PNI could be a predictor of recurrence outcome, and merits further investigation.
The benefits of postoperative adjuvant therapy in TSCC are a subject of research.The NCCN guidelines recommend that for patients with T1-2N0 oral cancer without risk factors, follow-up after surgery is feasible. 5Several studies have demonstrated insignificant benefits of adjuvant postoperative radiotherapy in early-stage TSCC. 20,40hile other studies found that OS of patients with oral cancer (T1-2N1) benefited from postoperative adjuvant therapy when the number of LND was <18 41 or when lymph node ratio (LNR) was >5.5% in OTSCC patients. 42ridman et al 20 also reported that adjuvant therapy significantly improved survival when there were positive/close margin for patients with T1-2N0M0 oral cavity squamous cell carcinoma.In this study, no survival improvement was notable for the pT1-2N0-1 TSCC patients with adjuvant therapy as a group, which may be related to the rare incidence of positive margins, high ratio of LND, less frequent LVI/PNI and the distribution of TNM stage categories among patients who underwent adjuvant therapy.Hence, we performed sub-group analysis and observed a trend for pT2 and pN1 patients which confirmed that adjuvant therapy may improve LRFS, reflecting the potential function of postoperative therapy for patients with more advanced stage disease.Similarly, another study also reported that postoperative radiotherapy may benefit patients with oral cancer in stage T1-2N1. 43Therefore, adjuvant therapy may be an important factor for improving survival outcome, especially when lymph node metastasis exists.
In this study, pathological differentiation emerged as the other independent factor that predicted OS, DFS, and LRFS in patients of T1-2N0-1M0 TSCC.Poorer differentiation was related with worse survival and more frequent recurrence.Several articles also observed same effect, showing that pathologic differentiation was associated with OS 13 and DFS 41,43 in oral cancer.Kim et al. 25 have reported pathologic differentiation as an independent factor for OS in patients of oral tongue cancer.Thus, histological grade may be a potential factor indicating the need for postoperative adjuvant therapy, and the patients with a lower degree of differentiation may need more stringent follow-up after treatment.
The findings of this study should be considered in light of its limitations.Firstly, the retrospective study design leads to inherent biases.Secondly, the TNM staging adopted in this study was based on the 7th but not the currently applied 8th AJCC classification system.Considering that a study involving more than 2000 patients found the upgraded classification was more likely to change stage at T3-4 and N2, 44 our adoption of the 7th AJCC edition classification for TSCC patients of T1-2N0-1 stage, particularly when 77.5% (341 out of 440) of the patients were in early stage (pT1-2N0M0), may bear less divergence owing to the choice of the classification edition.Furthermore, the low proportion of cases who received postoperative adjuvant therapy limits the strength of conclusions in this context.In addition, in cases of treatment interruption or loss to follow-up, which may be caused by patient non-cooperation, economic limitations, physical tolerance, or other reasons, the outcomes cannot be assessed accurately, and censoring can lead to overestimation of survival rates. 45owever, this relatively large sampled study analyzing clinical data collected in the short term (2014-2016) with a long follow-up presents valuable information for translating to clinical practice and research.Future prospective studies with large samples, deeper phenotyping and biomarker data are essential to design improved prognostic indices and precision medicine approaches.

| CONCLUSIONS
This was a single-center retrospective clinical study with a large sample size and long follow-up time.The results revealed that the clinical stage of cancer was a crucial factor for outcome primary resection of TSCC; earlier stages were associated with better prognosis.In addition, poor pathological differentiation emerged as a significant predictor affecting postoperative survival while existence of LVI/PNI was also a prognostic factor.High-quality LND (≥30) was beneficial for loco-regional control after surgery for patients with pT1cN0M0 or stage I TSCC, and thus may be recommended for these patients with earlystage disease to prolong recurrence-free time.

F I G U R E 1
LRFS in patients with pT2 and pN1 TSCC after surgery with or without adjuvant therapy.LRFS, local recurrence-free survival; TSCC, tongue squamous cell carcinoma.T A B L E 4 DFS and LRFS in T1cN0M0 or stage I postoperative TSCC patients with or without LND.

F I G U R E 2
LRFS in patients with pT1cN0 and stage I TSCC after surgery with or without LND.LRFS, local recurrence-free survival; TSCC, tongue squamous cell carcinoma.